This SCCOR proposal encompasses and interrelates approaches to ventilator-associated lung injury (VALI) ranging from genetic and molecular mechanisms, through cellular responses and animal models, and finally to cohort human studies. Large animal models of VALI are a crucial component of this continuum because they capture the heterogeneity of lung mechanical dysfunction found in human acute lung injury (ALl). The function of the "Canine Models" Core is to provide the project leaders in this SCCOR with large animal models of acute lung injury, with state-of-the-art evaluation of cardio-pulmonary pathophysiology, interventions, data analysis, and interpretation, in order to provide insight into the efficacy and mechanisms of clinically relevant management approaches and to facilitate the translation of basic research to the clinical arena. The Core will have the capability to implement several lung injury models, manage mechanical ventilation with conventional and novel techniques, and monitor gas exchange, lung mechanics, fluid status, and hemodynamic function. A unique feature of the Core is our expertise with functional lung imaging using high-speed multi-slice computed tomography (CT), permitting the non-invasive measurement of regional lung mechanics, aeration, lung water, and ventilation and perfusion distributions. Additionally, in conjunction with the Genomics and Biomarkers Cores, we will develop and validate a new methodology for canine genomic analysis in acute lung injury. These results will be used to develop novel genomic and proteomic biomarkers which will be available to all projects. The combination of these methods will allow the SCCOR investigators to characterize the effects of ventilator management protocols and pharmacologic interventions on regional lung function and cellular responses, and to relate these changes to the local mechanical stresses and regional physiology measured with functional CT imaging. By providing large animal genomic and proteomic tools previously available only in rodent models, it will be possible to evaluate promising discoveries and test hypotheses in disease models with clinically relevant mechanical heterogeneity and scale, a necessary step in the translation of basic science to clinical study and practice.